Anti-viral compositions

ABSTRACT

The anti-viral effectiveness of conventional anti-viral agents such as acyclovir, idoxuridine, vidarabine etc. is enhanced by formulation or administration with a physiologically acceptable lithium salt.

This application is a continuation, of application Ser. No. 07/159,128,filed Feb. 23, 1988 now U.S. Pat. No. 4,886,670, which is a continuationof Ser. No. 060,857, filed June 12, 1987 abandoned; which is acontinuation of Ser. No. 939,965, filed Dec. 10, 1986 abandoned; whichis a continuation of Ser. No. 846,094, filed Mar. 31, 1986 abandoned;which is a continuation of Ser. No. 743,394, filed June 11, 1985abandoned; which is a continuation of Ser. No. 628,270, filed July 6,1984 now abandoned.

This invention relates to novel compositions which be used for thetreatment of viral infections in man and animals, as well as to a methodof such treatment.

A large number of compounds have been found to exhibit in vitroanti-viral activity but only a few of these compounds have so far beenfound to be active in vivo. Examples of compounds which have been foundto be active, to varying degrees of success, in the treatment of viralinfections include amantadine, interferons, isoprinosine, cytarabine,idoxuridine, vidarabine and acyclovir. However, it has been found thatviruses are capable of developing resistance to many of the anti-viralagents currently in use. For example, concern has recently beenexpressed in the medical literature over the emergence of strains ofherpes simplex viruses which are resistant to acyclovir.

The in vitro ability of lithium compounds to prevent viral replication,notably of DNA viruses, at concentrations which do not destroy hostcells has been described by Skinner et al., Med. Microbiol. Immunol.168, 139-48, 1980. I have found that topically appliedlithium-containing compositions are highly effective in reducing thepain and irritation associated with herpes virus infections such as coldsores and genital herpes. The nature of the anion associated with thelithium ion in such compositions does not appear to be important,provided of course that the anion is physiologically acceptable andpermits bioavailability of the lithium ions.

I have now surprisingly found that viruses do not become resistant tolithium compounds on repeated exposure thereto. This implies that themechanism for anti-viral activity of lithium differs from the mechanismfor the activity of the known anti-viral agents. In order to reduce therisk of the emergence of resistant viral strains, I therefore proposethe conjoint use of a lithium compound with one or more other anti-viralcompounds in the treatment of viral infections, since it is unlikelythat the infecting virus would become resistant where the mechanisms foranti-viral activity of the compounds differ. I also believe that theconjoint administration of the compounds will increase anti-viralactivity.

In one aspect, therefore, the invention provides a pharmaceuticalcomposition comprising as active ingredients an effective amount of atleast one physiologically acceptable lithium salt together with aneffective amount of at least one other anti-viral compound.

In another aspect, the invention provides a method for the treatment ofa viral infection in a human or warm-blooded animal subject whichcomprises conjointly administering to said subject an effective amountof least one physiologically acceptable lithium salt together with aneffective amount of at least one other anti-viral compound.

Lithium salts have been safely used for many years in the treatment ofmanic-depressive psychosis, the lithium salt being orally administeredin an amount sufficient to maintain a blood lithium ion concentration ofthe order of 0.8 to 1 millimolar. However, such concentrations aregenerally not sufficient to exhibit a significant level of anti-viralactivity, since it has been found that higher lithium ion concentrationsare generally required to inhibit viral replication. Thus, in the methodof the invention anti-virally effective blood lithium ion concentrationsmay be achieved by oral or parenteral administeration without inducingany serious toxicity problems, as the body may be able to tolerate forshort periods much higher concentrations of lithium than would beacceptable in the treatment of manic depression, where administrationmay be necessary over many years or even decades.

The invention is however particularly preferred for the treatment ofviral infections by topical administration of the lithium salt with theother anti-viral agent(s). In this way, local concentrations of lithiumions sufficient to be lethal to the infecting virus may be achievedwithout unduly raising the blood lithium ion concentration. I have forexample, found that on topical administration of a lithium containingcomposition for up to 7 days, the plasma concentration of lithium isconsistently less than 0.1 millimolar. This indicates that the use oflithium salts in topical compositions is very safe, and this safety,coupled with my discovery of the ability of lithium to block viralreplication without inducing resistance, makes lithium particularlysuitable for combination with other anti-viral agents.

Examples of other anti-viral agents which may be used in thecompositions and method according to the invention include amantadine,interferons, isoprinosine, cytarabine, idoxuridine, vidarabine andacyclovir. These compounds may be incorporated into compositionsaccording to the invention in anti-virally effective amounts, e.g.amounts as known in the art, and advantageously make up from 0.01 to30%, preferably 0.2 to 10%, by weight of the compositions.

Any physiologically acceptable lithium salt may be used according to theinvention since, as indicated above, the nature of the anion in the saltis not believed to be important. Examples of such salts include lithiumchloride, succinate, citrate, acetylsalicylate and orotate. Thecompositions for use according to the invention conveniently containfrom 0.01 to 30%, and preferably 0.2 to 5%, by weight of lithium ions.

Compositions according to the invention may conveniently take the formof, for example, tablets, capsules, solutions, emulsions, syrups,suspensions, lotions, creams, ointments, gels, powders andsuppositories. As indicated above, compositions adapted for topicaladministration are particularly preferred.

Viral infections which may be treated according to the inventioninclude, for example, those due to herpes simplex or herpes zosterviruses. In particular, topical administration according to theinvention may be used in the treatment of herpes labialis, herpesgenitalis or shingles.

I have established that lithium salts do not cause the emergence ofresistant virus strains by determining dose-response curves for theaction of lithium ions against type-2 herpes simplex virus in babyhamster kidney cells. Viral replication is barely detectable at lithiumconcentrations of 24 millimolar and does not occur at concentrationsabove that figure. In my studies, the virus was therefore passagedthrough lithium by inoculating layers of baby hamster kidney cells andculturing for 48 hours in the presence of a medium containing 6, 12 or24 millimolar lithium ions. The monolayers were then washed, harvestedand virus yields estimated by a plaque technique. Passage was repeated15 times in lithium chloride. At the end of this time sensitivity of thevirus to lethal concentrations of lithium ions was tested. The virus wasfound to be just as sensitive as before passage, thus indicating thatthere had been no development of resistance. Similar results wereobtained using a strain of type-1 herpes simplex virus.

I have also found that when patients are topically treated with lithiumsuccinate ointment for recurrent genital herpes infections, there is noevidence of the development of resistance in virus harvested from thelithium-treated lesions on the 4th or 5th day of infection and testedagainst lithium in vitro.

The following examples serve to illustrate compositions according to theinvention. All percentages are by weight.

EXAMPLE 1 Ointment

    ______________________________________                                        Acyclovir        5%                                                           Lithium succinate                                                                              8%                                                           Lanolin base     87%                                                          ______________________________________                                    

EXAMPLE 2 Aqueous Cream

    ______________________________________                                        Idoxuridine       10%                                                         Lithium citrate   10%                                                         Aqueous cream base                                                                              80%                                                         ______________________________________                                    

EXAMPLE 3 Lotion

    ______________________________________                                        Acyclovir        10%                                                          Lithium chloride 12%                                                          Lotion base      78%                                                          ______________________________________                                    

EXAMPLE 4 Aqueous cream

    ______________________________________                                        Interferon         1%                                                         Lithium acetylsalicylate                                                                         6%                                                         Aqueous cream base 93%                                                        ______________________________________                                    

EXAMPLE 5 Ointment

    ______________________________________                                        Vidarbine        5%                                                           Lithium succinate                                                                              7%                                                           Lanolin base     88%                                                          ______________________________________                                    

I claim:
 1. A pharmaceutical composition comprising as activeingredients an effective synergistic amount of at least onephysiologically acceptable lithium salt together with an anti-virallyeffective amount of vidarabine.
 2. A composition as claimed in claim 1wherein said lithium salt is selected from the group consisting oflithium chloride, lithium succinate, lithium citrate, lithiumacetylsalicylate and lithium orotate.
 3. A composition as claimed inclaim 1 containing from 0.01 to 30% by weight of lithium ions.
 4. Acomposition as claimed in claim 1 containing from 0.2 to 10% by weightof vidarabine.
 5. A method for the treatment of a viral infection in ahuman or warm-blooded animal subject which comprises conjointlyadministering to said subject an effective synergistic amount of atleast one physiologically acceptable lithium salt together with ananti-virally effective amount of vidarabine.
 6. A method as claimed inclaim 5 wherein said lithium salt is selected from the group consistingof lithium chloride, lithium succinate, lithium citrate, lithiumacetysalicylate and lithium orotate.
 7. A method as claimed in claim 5wherein said lithium salt and vidarabine are topically administered toherpes lesions.